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1.
Microcirculation ; 24(6)2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28177171

RESUMEN

OBJECTIVE: Reduced skin flap survival due to ischemia is a serious concern during reconstructive cosmetic surgery. The absence of VEGF and its receptors during ischemia may lead to flap failure. We identified Peli1, a 46-kDa protein, as a proangiogenic molecule and is directly regulated by VEGF. Therefore, we hypothesized that Peli1 acts downstream of Flk-1/VEGFR2 and aids in skin flap survival during ischemia. METHODS: Scratch and matrigel assays were performed to observe cell proliferation, migration, and tube formation in vitro. Western blot analysis was carried out to detect the phosphorylation of Akt (p-Akt) and MAPKAPK2 (p-MK2) in HUVECs. The translational potential of Peli1 pretreatment in the rescue of skin flap tissue was studied in vivo using Flk-1+/- mice. Animals underwent dorsal ischemic skin flap surgery, and the tissue was collected on day 12 for analysis. RESULTS: Western blot analysis revealed a direct relationship between Peli1 and VEGF, as demonstrated by loss-of-function and gain-of-function studies. In addition, pretreatment with Ad.Peli1 restored the phosphorylation of Akt and MK2 and improved the migration potential of Flk-1-knockdown cells. Ad.Peli1 pretreatment salvaged the ischemic skin flap of Flk-1+/- mice by increasing blood perfusion and reducing the inflammatory response and the extent of necrosis. CONCLUSION: Our findings reveal that Peli1 is a proangiogenic molecule that acts downstream of VEGF-Flk-1 and restores angiogenesis and enhances skin flap survivability.


Asunto(s)
Proteínas Nucleares/farmacología , Colgajos Quirúrgicos/patología , Ubiquitina-Proteína Ligasas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/genética , Inductores de la Angiogénesis , Animales , Movimiento Celular/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana , Humanos , Isquemia , Ratones , Proteínas Nucleares/uso terapéutico , Piel/irrigación sanguínea , Piel/patología , Colgajos Quirúrgicos/irrigación sanguínea , Ubiquitina-Proteína Ligasas/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo
2.
Microvasc Res ; 97: 181-8, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25446011

RESUMEN

BACKGROUND: There is an emerging focus on investigating innovative therapeutic molecules that can potentially augment neovascularization in order to treat peripheral arterial disease (PAD). Although prolyl hydroxylase domain proteins 1 and 3 (PHD1 and PHD3) may modulate angiogenesis via regulation of hypoxia inducible factor-1α (HIF-1α), there has been no study directly addressing their roles in ischemia-induced vascular growth. We hypothesize that PHD1(-/-) or PHD3(-/-) deficiency might promote angiogenesis in the murine hind-limb ischemia (HLI) model. STUDY DESIGN: Wild type (WT), PHD1(-/-) and PHD3(-/-) male mice aged 8-12weeks underwent right femoral artery ligation. Post-procedurally, motor function assessment and laser Doppler imaging were periodically performed. The mice were euthanized after 28days and muscles were harvested. Immunohistochemical analysis was performed to determine the extent of angiogenesis by measuring capillary and arteriolar density. VEGF expression was quantified by enzyme-linked immunosorbent assay (ELISA). Bcl-2 and HIF-1α were analyzed by immunofluorescence. Fibrosis was measured by picrosirius red staining. RESULTS: PHD1(-/-) and PHD3(-/-) mice showed significantly improved recovery of perfusion and motor function score when compared to WT after femoral artery ligation. These mice also exhibited increased capillary and arteriolar density, capillary/myocyte ratio along with decreased fibrosis compared to WT. VEGF, Bcl-2 and HIF-1α expression increased in PHD1(-/-) and PHD3(-/-) mice compared to WT. CONCLUSIONS: Taken together these results suggest that PHD1 and PHD3 deletions promote angiogenesis in ischemia-injured tissue, and may present a promising therapeutic strategy in treating PAD.


Asunto(s)
Eliminación de Gen , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isquemia/metabolismo , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/metabolismo , Neovascularización Fisiológica , Procolágeno-Prolina Dioxigenasa/deficiencia , Animales , Modelos Animales de Enfermedad , Fibrosis , Miembro Posterior , Isquemia/genética , Isquemia/patología , Isquemia/fisiopatología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora , Músculo Esquelético/patología , Procolágeno-Prolina Dioxigenasa/genética , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Recuperación de la Función , Flujo Sanguíneo Regional , Factores de Tiempo , Factor A de Crecimiento Endotelial Vascular/metabolismo
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